CN113750051B - Solid andrographolide solution for oral administration and preparation method thereof - Google Patents
Solid andrographolide solution for oral administration and preparation method thereof Download PDFInfo
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Abstract
A solid andrographolide solution for oral administration is prepared through dissolving andrographolide in proper organic solvent, adding non-ionic surfactant, solid or semi-solid carrier material and crystallizing inhibitor, and porous adsorption to obtain solid powder containing andrographolide. The invention adopts porous materials to adsorb and solidify the liquid or semisolid delivery system, and the solidified solution can increase the stability of the medicine and improve the dissolution speed, dissolution rate and oral bioavailability of the medicine.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and relates to a solidified andrographolide solution for oral administration and a preparation method thereof.
Background
At present, improving the dissolution rate and bioavailability of insoluble drugs is a difficult problem in the field of pharmaceutical preparation research and drug production.
Andrographolide (An) is the main effective component of herba Andrographis, and belongs to diterpene lactone compound with molecular formula of C 20 H 30 NO 5 The relative molecular weight is 350.44, the melting point is 230-231 ℃, and the polymer is easily dissolved in acetone, methanol and ethanol, slightly dissolved in chloroform and diethyl ether and hardly dissolved in water.
Andrographolide is poorly soluble in water, resulting in slow absorption of the drug in vivo, low bioavailability, and extremely bitter taste, and is prone to emesis when administered orally. In recent years, a great deal of research has been devoted to the modification of its formulation to improve the dissolution and oral availability of andrographolide in water.
Different hydrophilic groups are introduced into the structure of andrographolide, so that the water solubility of the andrographolide is enhanced, and the administration by an injection way is realized, which is an effective way for improving the bioavailability of the andrographolide, and the varieties applied to clinic at present are potassium dehydroandrographolide succinate, lianbizhi, xiyanping and the like. Research shows that the structural modification product is lower in chemical stability, safety and effectiveness than the parent compound, and certain allergic reaction and toxic and side effects can occur in the clinical use process.
At present, the method for improving the bioavailability of andrographolide can be realized by selecting proper carriers and technologies, such as inclusion technology, superfine grinding technology, solid dispersion technology, molecular emulsification technology, liposome technology and the like, besides the method for improving physicochemical properties by changing molecular structures. However, these methods have drawbacks, for example, some inclusion materials may change the pharmacokinetic properties, tissue distribution properties, etc. of the main drug to a different extent, which may lead to safety and efficacy problems; micronization increases the free energy of the surface, accelerates the spontaneous aggregation trend of the medicine, and reduces the micronization effect; after the solid dispersion is placed for a period of time, aging phenomena such as drug dissolution reduction, crystallization precipitation or crystallization coarsening can occur; the emulsification technology has high cost due to the use of more emulsifying agents, has irritation to gastrointestinal mucosa or has chronic toxic effect on the whole body.
Liquid solidifying techniques refer to the conversion of a liquid drug or drug solution, drug suspension into a dry, non-adherent, well-flowing solid mixture by the addition of a specific solidifying carrier material. The liquid curing technology has the advantages of simple curing process, improved stability of the drug solution, improved dissolution rate of the drug, and the like. Andrographolide is prepared into solid solution by a liquid solidification technology, and is adsorbed and powdered by a porous material, so that the in-vitro dissolution rate of the andrographolide is improved, and a theoretical basis is laid for developing an andrographolide preparation with higher bioavailability.
Disclosure of Invention
The invention aims to provide a solidified andrographolide solution for oral administration and a preparation method thereof. Compared with the commercially available dropping pill and the bulk drug, the solidified solution can quickly release the drug, and improves the dissolution rate and the oral bioavailability of the drug.
The invention adopts porous materials to adsorb and solidify the liquid or semisolid delivery system, so as to achieve the results of increasing the stability and improving the dissolution rate and dissolution rate of the medicine.
The invention is a medicine-containing solid powder which is prepared by dissolving andrographolide in a proper organic solvent, adding a nonionic surfactant, a solid or semisolid carrier material and a crystallization inhibitor, and passing through a porous adsorption material, wherein the medicine-containing solid powder can obviously improve the dissolution rate of the andrographolide.
The andrographolide is completely dissolved in organic solvent, solid or semisolid carrier material, nonionic surfactant and crystallization inhibitor are added, and heated and stirred until molten, and the medicine exists in amorphous form. The porous adsorption material is added for adsorption, the particle size of the medicine is reduced, the surface area is increased along with the particle size, and the thermodynamic activity in the medicine dispersing process is improved, so that the dissolution rate of the medicine is increased.
Specifically, the invention is realized by the following technical scheme:
a solidified andrographolide solution for oral administration comprises andrographolide, an organic solvent, a nonionic surfactant, a solid or semisolid carrier material, a crystallization inhibitor and a porous adsorption material, wherein the dosage of the solid or semisolid carrier material is 3-40% of the total mass of a prescription.
The organic solvent is selected from one or more of liquid polyethylene glycol, diethylene glycol monoethyl ether (Transcutol P), 1, 2-propylene glycol, absolute ethyl alcohol, N-methylpyrrolidone (NMP), dimethyl sulfoxide and dimethylformamide, preferably NMP.
The nonionic surfactant is selected from one or more of poloxamer 188 (F68), polyethylene glycol, povidone K12 (PVP K12), diethylene glycol monoethyl ether (Transcutol P), vitamin E polyethylene glycol succinate (TPGS), polysorbate 80 and polyoxyethylene castor oil derivatives, and the mass ratio of andrographolide to the nonionic surfactant is 1:0.2-1:2, preferably 1:0.5-1:1.
The solid or semisolid carrier material is selected from one or a mixture of poloxamer 407 (F127), polyethylene glycol and glyceryl behenate (compitol 888 ATO), and the mass ratio of andrographolide to the solid or semisolid carrier material is 1:1-1:6. The solid or semisolid carrier material is preferably polyethylene glycol 6000, and the ratio of andrographolide to polyethylene glycol 6000 is preferably 1:3-1:5.
In order to prevent recrystallization precipitation after drug dissolution and maintain drug concentration at a relatively stable level, a crystallization inhibitor (abbreviated as a crystallization inhibitor) is added to a drug-containing solidifying liquid in the present invention. The crystal inhibitor is selected from povidone K12 (PVP K12), copovidone VA64 (PVP VA 64), polycaprolactam-polyvinyl acetate-polyethylene glycol copolymer [ ]
) One or more of hydroxypropyl methylcellulose acetate succinate (HPMCAS), preferably +.>
The mass ratio of andrographolide to the crystallization inhibitor is 1:0.5-1:5, preferably 1:1-1:3.
The porous adsorption material is porous starch, and the porous adsorption material accounts for 50-90% of the total mass of the prescription.
The invention also aims to provide a preparation method of the solid andrographolide solution for oral administration, which comprises the following specific steps:
(1) Taking a prescribed amount of organic solvent and nonionic surfactant, adding andrographolide as a raw material medicine, and performing ultrasonic dissolution;
(2) Adding a solid or semi-solid carrier material and a crystallization inhibitor into the solution obtained in the step (1), heating and stirring until the solid or semi-solid carrier material and the crystallization inhibitor are melted;
(3) Adding porous adsorption material, stirring, mixing, and cooling to room temperature to obtain solid andrographolide solution.
The preparation method of the solidified andrographolide solution for oral administration comprises the following steps:
in the step (1), the nonionic surfactant is selected from one or more of poloxamer 188 (F68), polyethylene glycol, povidone K12 (PVP K12), diethylene glycol monoethyl ether (Transcutol P), vitamin E polyethylene glycol succinate (TPGS), polysorbate 80 and polyoxyethylene castor oil derivatives, and the mass ratio of the raw andrographolide to the nonionic surfactant is 1:0.2-1:2, preferably 1:0.5-1:1.
In the step (1), the organic solvent is selected from one or more of liquid polyethylene glycol, diethylene glycol monoethyl ether (Transcutol P), 1, 2-propylene glycol, absolute ethyl alcohol, N-methylpyrrolidone (NMP), dimethyl sulfoxide and dimethylformamide, preferably NMP.
In the step (2), the solid or semisolid carrier material is selected from one or a mixture of a plurality of poloxamer 407 (F127), polyethylene glycol and glyceryl behenate (compitol 888 ATO), and the mass ratio of the andrographolide bulk drug to the solid or semisolid carrier material is 1:1-1:6. The solid or semisolid carrier material is preferably polyethylene glycol 6000, and the ratio of the andrographolide bulk drug to the polyethylene glycol 6000 is preferably 1:3-1:5.
In the step (2), the crystallization inhibitor is selected from povidone K12 (PVP K12), copovidone VA64 (PVP VA 64), polycaprolactam-polyvinyl acetate-polyethylene glycol copolymer
A mixture of one or more of hydroxypropyl methylcellulose acetate succinate (HPMCAS), preferably +.>
The mass ratio of the andrographolide bulk drug to the crystal inhibitor is 1:0.5-1:5, preferably 1:1-1:3.
In the step (3), the porous adsorption material is porous starch, and the porous adsorption material accounts for 50-90% of the total mass of the prescription.
The dissolution rate inspection designed by the invention is carried out by adopting a device of a third method cup method of the dissolution rate and release rate measurement method of four parts of Chinese pharmacopoeia 2020 edition.
Determination of dissolution of solidified andrographolide solution for oral administration (non-sink conditions): and (3) a third method cup method for measuring the dissolution and release of four parts according to the 2020 edition of Chinese pharmacopoeia. 100g of dissolution medium (distilled water) was measured and poured into each dissolution cup, and the dissolution medium was heated to a temperature of 37.+ -. 0.5 ℃ and a rotation speed of 75r/min. 3g of the solution was aspirated at 5, 15, 30, 45, 60min, respectively, and immediately filled with isothermal and equivalent amounts of blank medium solution. The sample obtained was immediately filtered through a 0.22 μm microfiltration membrane, the primary filtrate was discarded, and the subsequent filtrate was diluted with methanol as appropriate and shaken well. 10 μl was measured by HPLC, and the cumulative percent drug elution was calculated.
Determination of dissolution of solidified andrographolide solution for oral administration (sink conditions): the method for measuring the dissolution rate of the andrographolide dripping pill is carried out according to the 2020 edition of Chinese pharmacopoeia. 200g of 1% sodium dodecyl sulfate solution is taken as a dissolution medium, the temperature of the dissolution medium is kept at 37+/-0.5 ℃ by heating, the rotating speed is 75r/min, 3g of the solution is respectively sucked in 5, 15, 30, 45 and 60min, and the isothermal and equivalent blank medium solution is immediately fed in. The sample obtained was immediately filtered through a 0.22 μm microfiltration membrane, the primary filtrate was discarded, and the subsequent filtrate was diluted with methanol as appropriate and shaken well. 10 μl was measured by HPLC, and the cumulative percent drug elution was calculated.
The solid andrographolide solution for oral administration prepared by the preparation method is matched with other auxiliary materials and is used for preparing conventional preparations, such as: tablets, capsules, granules and powders.
Compared with the prior art, the invention has the following advantages:
(1) The prescription has simple process and low production cost, has no special requirement on equipment, and is easy to realize large-scale production.
(2) The medicine solution and the low-melting point lipid material are blended into a mixed solution, and the mixed solution is cooled rapidly after being stirred uniformly to form a solidified solution, and the medicine exists in a solid matrix material in a molecular state, so that the dissolution rate of the medicine is obviously increased.
(3) By utilizing the adsorption function of the porous material, the dissolution rate and the dissolution rate of the medicine can be effectively controlled, the dissolution rate is not lower than 80% in 15min, and the dissolution rate is not lower than 90% in 30 min; the porous material is absorbed to make the medicine solution powder, and then the medicine solution is further pressed into tablets or filled into capsules, so that the medicine is convenient to store, and the preparation process and the prescription are simple. The stability of the medicine is improved, and the medicine is convenient to store.
(4) The solid andrographolide solution provided by the invention has good fluidity, can be further pressed into tablets or filled into capsules, has a simple and easy preparation method, is easy to accept by patients through oral administration, and increases the compliance of oral administration.
Drawings
Figure 1 comparison of in vitro dissolution profiles under sink conditions.
Figure 2 mean plasma concentration versus time curve in rats after dosing.
Detailed Description
Examples 1 to 9:
determination of solubility of andrographolide in different solvents
Adding andrographolide into PEG 200, PEG 400, PEG 600, transcutol P, 1, 2-propylene glycol, absolute ethyl alcohol, NMP, dimethyl sulfoxide and dimethylformamide respectively, grinding in a mortar for 15min, subpackaging into two EP pipes, respectively placing into a heat-collecting constant-temperature heating magnetic stirrer at 25 ℃ and 50 ℃ for 24h, centrifuging at 2000rpm for 10min, taking 5 drops of supernatant, accurately weighing, properly diluting with methanol, accurately measuring 10 mu L, injecting into a high performance liquid chromatograph for measurement, recording peak area, and calculating the solubility of andrographolide in different solvents. Specifically, the results are shown in Table 1.
TABLE 1 solubility of andrographolide in different solvents
From the above results, it was found that absolute ethanol has a low boiling point and volatilizes at 50 ℃, so that the solubility of andrographolide in absolute ethanol at 50 ℃ was not detected. In addition, the temperature has a relatively small influence on the solubility of andrographolide in NMP, and NMP is selected as a preferable solvent.
Examples 10 to 15:
f127 solidified andrographolide solution with different proportions
Prescription of prescription
Andrographolide 0.1g
NMP 400μL
F127 0.1～0.6g
Weighing 0.1g of andrographolide, adding 400 mu L of NMP for ultrasonic dissolution, then adding F127 with different masses, heating and stirring at 65 ℃ until the mixture is melted, stopping heating, and continuing stirring until the mixture is cooled and solidified to obtain the andrographolide solidified solution containing F127.
TABLE 3 addition of different proportions of F127 solidified andrographolide solutions at room temperature
| F127 addition amount | The obtained andrographolide solidified solution is in room temperature | |
| Example 10 | 0.1g | Is in a liquid state when placed at room temperature, and does not meet the requirement of a solid solution at room temperature. |
| Example 11 | 0.2g | Is in a liquid state when placed at room temperature, and does not meet the requirement of a solid solution at room temperature. |
| Example 12 | 0.3g | Is in a liquid state when placed at room temperature, and does not meet the requirement of a solid solution at room temperature. |
| Example 13 | 0.4g | Is in a liquid state when placed at room temperature, and does not meet the requirement of a solid solution at room temperature. |
| Example 14 | 0.5g | The solidification temperature is 26 ℃, and the product is placed at room temperature to be in a semisolid state, which shows that the stability is poor. |
| Example 15 | 0.6g | The solidification temperature is 26 ℃, and the product is placed at room temperature to be in a semisolid state, which shows that the stability is poor. |
Examples 16 to 21:
compritol 888ATO solidified andrographolide solution with different proportions
Prescription Andrographolide 0.1g
NMP 400μL
Compritol 888ATO 0.1～0.6g
Weighing 0.1g of andrographolide, adding 400 mu L of NMP for ultrasonic dissolution, then adding Compritol 888ATO with different mass, heating at 65 ℃ and stirring to melt, stopping heating and continuing stirring until cooling and solidifying to obtain the solid andrographolide solution containing Compritol 888 ATO.
TABLE 4 addition of Compritol 888ATO solid Andrographolide solutions at different proportions at room temperature
TABLE 5 results of in vitro Release of solidified andrographolide solution under non-sink conditions
Examples 22 to 39:
PEG-n solidified andrographolide solution with different proportions
Prescription of prescription
Andrographolide 0.1g
NMP 400μL
PEG-n 0.1～0.6g
Weighing 0.1g of andrographolide, adding 400 mu L of NMP for ultrasonic dissolution, then adding PEG-n with different masses, heating and stirring at 65 ℃ until the PEG-n is melted, stopping heating, and continuing stirring until cooling and solidifying to obtain the andrographolide solidified solution containing PEG-n.
TABLE 6 addition of PEG-n solidified andrographolide solutions at different ratios at room temperature
| PEG-n addition amount | The obtained andrographolide solidified solution is in room temperature | |
| Example 22 | PEG2000(0.1g) | Is in a liquid state when placed at room temperature, and does not meet the requirement of a solid solution at room temperature. |
| Example 23 | PEG2000(0.2g) | Is in a liquid state when placed at room temperature, and does not meet the requirement of a solid solution at room temperature. |
| Example 24 | PEG2000(0.3g) | The product is placed at room temperature to be in a semi-solid state, which indicates poor stability. |
| Example 25 | PEG2000(0.4g) | The product is placed at room temperature to be in a semi-solid state, which indicates poor stability. |
| Example 26 | PEG2000(0.5g) | The in vitro release results are shown in the following table with a setting temperature of 28℃and under non-sink conditions. |
| Example 27 | PEG2000(0.6g) | The in vitro release results are shown in the following table with a solidification temperature of 30℃and under non-sink conditions. |
| Example 28 | PEG4000(0.1g) | Is in a liquid state when placed at room temperature, and does not meet the requirement of a solid solution at room temperature. |
| Example 29 | PEG4000(0.2g) | The solidification temperature is 25 ℃, and the product is placed at room temperature to be in a semisolid state, which shows that the stability is poor. |
| Example 30 | PEG4000(0.3g) | The solidification temperature is 25 ℃, and the product is placed at room temperature to be in a semisolid state, which shows that the stability is poor. |
| Example 31 | PEG4000(0.4g) | The solidification temperature was 29℃and the semisolid state was observed when left at room temperature, indicating poor stability. |
| Example 32 | PEG4000(0.5g) | The in vitro release results are shown in the following table with a setting temperature of 33℃and under non-sink conditions. |
| Example 33 | PEG4000(0.6g) | The in vitro release results are shown in the following table with a setting temperature of 34℃and under non-sink conditions. |
| Example 34 | PEG6000(0.1g) | The solidification temperature is 25 ℃, and the product is placed at room temperature to be in a semisolid state, which shows that the stability is poor. |
| Example 35 | PEG6000(0.2g) | The solidification temperature is 25 ℃, and the product is placed at room temperature to be in a semisolid state, which shows that the stability is poor. |
| Example 36 | PEG6000(0.3g) | The solidification temperature is 28 ℃, and the product is placed at room temperature to be in a semisolid state, which shows that the stability is poor. |
| Example 37 | PEG6000(0.4g) | The in vitro release results are shown in the following table with a setting temperature of 32℃and under non-sink conditions. |
| Example 38 | PEG6000(0.5g) | The in vitro release results are shown in the following table with a setting temperature of 33℃and under non-sink conditions. |
| Example 39 | PEG6000(0.6g) | The in vitro release results are shown in the following table with a setting temperature of 35℃and under non-sink conditions. |
TABLE 7 results of in vitro Release of solidified andrographolide solution under non-sink conditions
Examples 40 to 43:
determination of solubility of Andrographolide in NMP after Transcutol P addition
Prescription Andrographolide 1.5g
Transcutol P 0.3～3.0g
NMP 2.0g
1.5g of andrographolide is weighed into a mortar, transcutol P of different masses is added, grinding is carried out for 15min, and grinding is continued for 15min after 2.0g of NMP is added. The ground suspension is split-packed into two EP tubes, and is respectively placed in a heat-collecting constant-temperature heating magnetic stirrer at 25 ℃ and 50 ℃ for centrifugation at 2000rpm for 10min, 5 drops of supernatant are precisely weighed, and are properly diluted by methanol, 10 mu L of the supernatant is precisely measured and injected into a high performance liquid chromatograph for measurement, the peak area is recorded, and the solubility of andrographolide in NMP after being added into Transcutol P at 25 ℃ and 50 ℃ is calculated.
TABLE 8 determination of solubility of andrographolide in NMP after Transcutol P addition
Examples 44 to 47:
determination of solubility of Andrographolide in NMP after addition of PVP K12
Prescription Andrographolide 1.5g
PVP K12 0.3～3.0g
NMP 2.0g
1.5g of andrographolide was weighed into a mortar, PVPK12 of different masses was added, and after grinding for 15min, 2.0g of NMP was added and grinding was continued for 15min. Split charging the ground suspension into two EP tubes, respectively placing in a heat-collecting constant-temperature heating magnetic stirrer at 25 ℃ and 50 ℃ for 24 hours, centrifuging at 2000rpm for 10 minutes, taking 5 drops of supernatant, precisely weighing, properly diluting with methanol, precisely measuring 10 mu L of the supernatant, injecting into a high performance liquid chromatograph for measurement, recording peak areas, and calculating the solubility of andrographolide in NMP (N-methyl pyrrolidone) after adding PVP K12 at 25 ℃ and 50 ℃.
TABLE 9 determination of solubility of andrographolide in NMP after addition of PVP K12
Examples 48 to 51:
determination of solubility of Andrographolide in NMP after addition of TPGS
Prescription Andrographolide 1.5g
TPGS 0.3～3.0g
NMP 2.0g
1.5g of andrographolide was weighed into a mortar, TPGS of different masses was added, and after grinding for 15min, 2.0g of NMP was added, and grinding was continued for 15min. The ground suspension is split-packed into two EP tubes, and is respectively placed in a heat-collecting constant-temperature heating magnetic stirrer at 25 ℃ and 50 ℃ for centrifugation at 2000rpm for 10min, 5 drops of supernatant are taken and precisely weighed, and are properly diluted by methanol, 10 mu L of the supernatant is precisely measured and injected into a high performance liquid chromatograph for measurement, the peak area is recorded, and the solubility of andrographolide in NMP (N-methyl pyrrolidone) after being added into TPGS at 25 ℃ and 50 ℃ is calculated.
TABLE 10 determination of solubility of andrographolide in NMP after addition of TPGS
Examples 52 to 63:
determination of solubility of Andrographolide in NMP after PEG-n addition
Prescription Andrographolide 1.5g
PEG-n 0.3～3.0g
NMP 2.0g
1.5g of andrographolide is weighed into a mortar, PEG-n of different masses is added, grinding is carried out for 15min, 2.0g of NMP is added, and grinding is continued for 15min. The ground suspension is split-packed into two EP tubes, and is respectively placed in a heat-collecting constant-temperature heating magnetic stirrer at 25 ℃ and 50 ℃ for centrifugation at 2000rpm for 10min, 5 drops of supernatant are taken and precisely weighed, and are properly diluted by methanol, 10 mu L of the supernatant is precisely measured and injected into a high performance liquid chromatograph for measurement, the peak area is recorded, and the solubility of andrographolide in NMP (N-methyl pyrrolidone) at 25 ℃ and 50 ℃ after PEG 200 is added is calculated.
TABLE 11 determination of solubility of andrographolide in NMP after PEG-n addition
Examples 64-67:
determination of solubility of Andrographolide in NMP after Polysorbate 80 addition
Prescription Andrographolide 1.5g
NMP 2.0g
1.5g of andrographolide is weighed into a mortar, polysorbate 80 of different masses is added, grinding is carried out for 15min, and grinding is continued for 15min after 2.0g of NMP is added. The ground suspension is split-packed into two EP tubes, and is respectively placed in a heat-collecting constant-temperature heating magnetic stirrer at 25 ℃ and 50 ℃ for centrifugation at 2000rpm for 10min, 5 drops of supernatant are precisely weighed, and are properly diluted by methanol, 10 mu L of the supernatant is precisely measured and injected into a high performance liquid chromatograph for measurement, the peak area is recorded, and the solubility of andrographolide in NMP (N-methyl pyrrolidone) after polysorbate 80 is added at 25 ℃ and 50 ℃ is calculated.
Table 12 determination of solubility of andrographolide in NMP after addition of polysorbate 80
Examples 68 to 71:
determination of solubility of Andrographolide in NMP after addition of polyoxyethylated Castor oil derivatives
Prescription Andrographolide 1.5g
0.3 to 3.0g of polyoxyethylated castor oil derivative
NMP 2.0g
1.5g of andrographolide is weighed into a mortar, polyoxyethylated castor oil derivatives with different masses are added, grinding is carried out for 15min, and grinding is continued for 15min after adding 2.0g of NMP. The ground suspension is split-packed into two EP tubes, and is respectively placed in a heat-collecting constant-temperature heating magnetic stirrer at 25 ℃ and 50 ℃ for centrifugation at 2000rpm for 10min, 5 drops of supernatant are precisely weighed, and are properly diluted by methanol, 10 mu L of the supernatant is precisely measured and injected into a high performance liquid chromatograph for measurement, the peak area is recorded, and the solubility of andrographolide in NMP (N-methyl pyrrolidone) at 25 ℃ and 50 ℃ after polyoxyethylene castor oil derivatives are added is calculated.
Table 13 determination of solubility of andrographolide in NMP after addition of polyoxyethylated castor oil derivatives
Examples 72 to 77:
dissolution measurement of solidified andrographolide solution added with crystallization inhibitor HPMCAS
Weighing 0.1g of andrographolide, adding 400 mu L of NMP for ultrasonic dissolution, then adding 0.5g of PEG 6000 and HPMCAS with different mass, heating and stirring at 65 ℃ until the andrographolide is melted, stopping heating and stirring until cooling and solidifying are carried out, thus obtaining the solidified andrographolide solution. The results of in vitro release for different time periods under non-sink conditions are shown in the following table.
TABLE 14 dissolution measurement of solidified andrographolide solution with addition of crystallization inhibitor HPMCAS
Examples 78 to 83:
determination of dissolution of solidified andrographolide solution with crystallization inhibitor PVP K12
Weighing 0.1g of andrographolide, adding 400 mu L of NMP for ultrasonic dissolution, then adding 0.5g of PEG 6000, heating and stirring PVP K12 with different masses at 65 ℃ until the mixture is melted, stopping heating, and continuing stirring until the mixture is cooled and solidified to obtain the solidified andrographolide solution. The results of in vitro release for different time periods under non-sink conditions are shown in the following table.
TABLE 15 determination of dissolution of solidified andrographolide solution with added crystallization inhibitor PVP K12
Examples 84 to 89:
dissolution measurement of solid andrographolide solution added with crystallization inhibitor PVP VA64
Weighing 0.1g of andrographolide, adding 400 mu L of NMP for ultrasonic dissolution, then adding 0.5g of PEG 6000, heating and stirring PVP VA64 with different mass at 65 ℃ until melting, stopping heating and continuing stirring until cooling and solidifying to obtain the solidified andrographolide solution. The results of in vitro release for different time periods under non-sink conditions are shown in the following table.
Table 16 determination of dissolution of solidified andrographolide solution with addition of crystallization inhibitor PVP VA64
Examples 90 to 95:
dissolution measurement of solidified andrographolide solution with crystallization inhibitor
Weighing 0.1g of andrographolide, adding 400 mu L of NMP, performing ultrasonic dissolution, and then adding 0.5g of PEG 6000 with different quality
Heating at 65deg.C, stirring to melt, stopping heating, and stirring until cooling and solidifying to obtain solidified andrographolide solution. The results of the release in vitro for different time periods under non-sink conditions are shown in the following table. TABLE 17 determination of dissolution of solidified andrographolide solution with added crystallization inhibitor PVPVA64
Therefore, the crystal inhibitor is preferably
Examples 96 to 101:
in vitro release assay of solidified andrographolide solution using porous starch as adsorbent
Weighing 0.1g of andrographolide, adding 400 mu LNMP, dissolving by ultrasonic wave, and adding
0.5And g, heating and stirring PEG 6000 at 65 ℃ until the PEG 6000 is melted, adding porous starch in proportion for multiple times, adsorbing all molten liquid into porous starch particles under the mechanical grinding action in a mortar, stopping heating, and continuously grinding until the mixture is cooled to obtain andrographolide solidified liquid porous starch particles. The results of in vitro release under non-sink conditions and sink conditions are shown in the following table.
TABLE 18 determination of in vitro Release of solid andrographolide solutions Using porous starch as adsorbent
Examples 102-107:
solid andrographolide solution prescription using porous starch as adsorbent
Weighing 0.1g of andrographolide, adding 400 mu L of NMP for ultrasonic dissolution, adding other auxiliary materials except porous starch in a prescription amount, heating and stirring at 65 ℃ until the auxiliary materials are molten, adding porous starch in a plurality of times according to a proportion, mechanically grinding the work in a mortar, adsorbing all molten liquid into porous starch particles, stopping heating, and continuously grinding until the mixture is cooled to obtain the porous starch particles of the andrographolide solidified liquid. The results of in vitro release under non-sink conditions and under sink conditions are shown in the following table.
Table 19 prescription of solidified andrographolide solution Using porous starch as adsorbent
As can be seen from the dissolution results, compared with the bulk drugs or the commercial preparations, the preparation prepared by the preparation process provided by the invention has the advantage that the oral bioavailability is obviously improved.
The in vitro dissolution profile of the andrographolide solidified solution prepared in example 103 above, and the commercially available dripping pill and drug substance under the condition of sink is shown in fig. 1, and the bioavailability after oral administration of rats is shown in fig. 2. As shown in figures 1 and 2, compared with the commercially available dropping pills and raw medicines, the andrographolide solidifying solution provided by the invention has the advantages of higher release speed, higher accumulated release amount and higher in-vivo bioavailability.
Claims (4)
1. A solidified andrographolide solution for oral administration, comprising andrographolide, an organic solvent, a nonionic surfactant, a solid or semi-solid carrier material, a crystallization inhibitor, and a porous adsorption material;
the organic solvent is N-methyl pyrrolidone;
the nonionic surfactant is poloxamer 188, and the mass ratio of andrographolide to the nonionic surfactant is 1:0.2-1:2;
the solid or semisolid carrier material is polyethylene glycol 6000, and the mass ratio of andrographolide to the solid or semisolid carrier material is 1:1-1:6;
the porous adsorption material is porous starch, and the porous adsorption material accounts for 50% -90% of the total mass of the prescription;
the crystallization inhibitor is polycaprolactam-polyvinyl acetate-polyethylene glycol copolymer, and the mass ratio of andrographolide to the crystallization inhibitor is 1:0.5-1:5;
the solid andrographolide solution for oral administration is a drug-containing solid powder which is prepared by dissolving andrographolide in an organic solvent, adding a nonionic surfactant, a solid or semisolid carrier material and a crystallization inhibitor, and performing porous adsorption material to obtain the solid powder capable of remarkably improving the dissolution rate of the andrographolide;
according to the third method of four-part dissolution and release measurement method of Chinese pharmacopoeia 2020 edition, the dissolution rate of the solid andrographolide solution for oral administration is not lower than 80% in 15min and not lower than 90% in 30 min.
2. The solution of solidified andrographolide for oral administration according to claim 1, wherein the ratio of andrographolide to polyethylene glycol 6000 is 1:3-1:5.
3. The solution of solidified andrographolide for oral administration according to claim 1, wherein the solution of solidified andrographolide for oral administration is prepared into a dry suspension, a capsule or a tablet form by adopting a pharmaceutical preparation technology for clinical treatment application.
4. A method for preparing the solidified andrographolide solution for oral administration according to any one of claims 1 to 3, comprising the steps of:
(1) Taking a prescribed amount of organic solvent and nonionic surfactant, adding andrographolide as a raw material medicine, and performing ultrasonic dissolution;
(2) Adding a solid or semi-solid carrier material and a crystallization inhibitor into the solution obtained in the step (1), heating and stirring until the solid or semi-solid carrier material and the crystallization inhibitor are melted;
(3) Adding porous adsorption material, stirring, mixing, and cooling to room temperature to obtain solid andrographolide solution.
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